One of the biggest challenges we face in the development of a prophylactic vaccine against HIV/AIDS is to design an envelope (Env) immunogen that can induce protective neutralizing antibodies effective against the diversity of virus strains that characterize the global pandemic. We propose to evaluate novel candidate envelope (Env) vaccines that can induce potent, durable, and broadly protective neutralizing antibody and T cell responses against HIV. The central hypothesis that we seek to test if successful in the proposed research is the following: A vaccine composition that raises potent and durable neutralizing antibody responses with broad reactivity against a diverse primary HIV-1 isolates will protect against HIV infection. The three major objectives are: 1) Using the tools of modern structural biology and biochemistry, to design, produce, and characterize in vitro novel Env immunogens;2) To identify structures and formulations that can induce potent, broad, and durable neutralizing antibody and T-cell responses in vivo in animal models;and 3) To identify candidate Env vaccines that can induce broad immunity and protection in non-human primate virus challenge models. The program comprises 3 projects and 3 scientific cores plus an Administrative Core that will manage the consortium. The three projects will focus on complementary strategies to design novel HIV Env immunogens for the induction of broadly reactive neutralizing antibodies based on current structural information regarding HIV-1 envelope surface (gp120) and transmembrane (gp41) glycoproteins. The scientific cores will be: the Vaccine Technologies Core and the Nonhuman Primate Studies Core and the Peptide Structure and Dynamics Core. Novel delivery scaffolds, adjuvants, and viral vector delivery systems, will be employed to deliver peptide-based and protein antigens. Antigenic structures will be characterized using atomic force microscopy (AFM) to determine their overall size and structure, and cryogenic electron microscopy (EM) will be used to achieve 3D reconstructions with angstrom level resolution. These analyses should provide molecular level understanding of the structures and interactions that lead to enhanced immune responses. Overall, this program should provide for the performance of well-controlled comparative in vitro and in vivo evaluations of the proposed vaccines. Env immunogens will be systematically screened in small animals and non-human primate vaccine/challenge studies using well-defined immunologic and virologic endpoints. These efforts are expected to lead to the identification of improved candidate vaccines for future clinical evaluations.